Alzheimer's disease is a progressive neurodegenerative disorder which causes irreversible damage to brain cells leading to dementia and ultimately death. It is characterized by formation of amyloid plaques and neurofibrillary tangles in the brain. Currently, it is primarily diagnosed by exclusion of other known causes of dementia. Diagnosis at an early stage prior to irreversible changes is practically non-existent.
In order for a therapeutic intervention to be significantly effective, it will have to be administered very early on prior to irreversible changes.
Accordingly, a non-invasive diagnostic test for early diagnosis of Alzheimer's disease would be a most welcomed addition to the diagnostician's armamentarium.
Calcium-dependent potassium channels have been found to be implicated with Alzheimer's disease. Abnormalities of potassium (K.sup.+) channel function have been reported in cultured cells in Alzheimer's disease (AD).sup.1.
Depending upon the single channel conductance, a calcium-dependent potassium (K.sub.Ca) channel is termed high-conductance or maxi-K (100-250 picosiemens (pS)), intermediate-conductance (18-50 pS), or low-conductance (10-14 pS)K.sub.Ca.sup.2.
The high conductance K.sub.Ca is present in neurons, cardiac cells and various types of smooth muscles.sup.3. The intermediate-conductance channel has been shown to be present in red blood cells.sup.4, and in smooth muscle.sup.5. The low-conductance channel is present in a variety of cell types.sup.6.
The most important tools to distinguish between low-and high-conductance K.sub.Ca are the toxins apamin.sup.7, and charybdotoxin.sup.8.
Atwal, footnote 2 at page 581, points out that "while charybdotoxin specifically blocks maxi-K, apamin is a potent blocker of the low conductance K.sub.Ca. However, in certain tissues, for example, rat brain, charybdotoxin may block K.sub.Ca of all three types."
Mahaut-Smith.sup.8a discloses that blood platelets contain a 30 pS conductance charybdotoxin-sensitive channel.
It is also known that iberiotoxin specifically inhibits maxi-K channels (Elelvez et al.sup.8b).
A 113 pS K.sup.+ channel sensitive to tetraethylammonium has been described as being absent or not functional in cultured fibroblasts from patients with AD.sup.9, and this defect was mimicked in normal fibroblasts by the addition of amyloid beta-protein (A.beta.).sup.10, which is also plentiful in platelets.sup.11,12. However, tetraethylammonium is not a selective inhibitor of K.sup.+ channels, and so the pharmacological identity of the abnormal channel in cultured fibroblasts is not clear.
U.S. Pat. No. 5,580,748 to Alkon et al (issued Dec, 3, 1996) discloses a method for the diagnosis of Alzheimer's disease using human cells such as fibroblasts, buccal mucosal cells, neurons, and blood cells such as erythrocytes, lymphocytes and lymphoblastoid cells, wherein the absence of a functional 133 pS potassium channel in the test cells indicates the presence of Alzheimer's disease. Tetraethylammonium is employed as a potassium channel blocker to aid in detecting the presence of the functioning 113 pS potassium channel.